The replacement of dopamine (DA) neurons by transplanting fetal ventral midbrain is a potential restorative therapy for Parkinson's disease (PD). Embryonic stem (ES) cells are a realistic alternative to fetal cells for cell-based replacement therapies since they are renewable, can be controlled for cell type specificity and reproducibility of in vitro processing. We have derived DA neurons from primate and human ES cell sources. In this project we will determine the therapeutic potential of immature post-mitotic DA neurons derived from human ES cells by transplantation into a MPTP PD primate model. The MPTP primate model produced by chronic systemic infusions is currently the best available functional model for PD and L-DOPA related complications. These MPTP-treated primates develop the characteristic motor signs of the human disease, that also improve with L-DOPA in the model. As seen in PD patients, repeated L-DOPA administration induces abnormal involuntary movements; the L-DOPA induced dyskinesias. First, we will examine the capacity of transplanted post-mitotic DA neurons derived from human ES cells to improve PD signs in MPTP primates, in comparison to standard L-DOPA therapy. Detailed motor behavioral evaluation, functional neuroimaging using PET specific DA radiotracers and functional MRI will determine the functional effects of the transplanted DA neurons. Such data is then analyzed in conjunction with post mortem analyses of transplant cell composition, host reactions and connectivity. Aim 2, determines the effects of the transplanted DA phenotype derived from primate ES cells (not requiring immune suppression) on dyskinesias. Dyskinesias are induced by repeated L-DOPA administration in stable MPTP PD model primates and then rated systematically before and after transplantation. Functional imaging studies in such animals will also be performed to examine maturation and functional integration of ES derived DA neurons into the host circuitry. The data, conclusion and hypotheses generated and data are analyzed further by addressing the corresponding the clinical and histological studies of transplanted PD patients (with human fetal DA neurons) performed in the neurohistology core. The PD focused work in this project is necessary to determine the growth, functional benefits and safety of human and primate ES cell derived DA neurons in a primate model of PD, in order to potentially translate the experimental hypothesis into clinically effective and safe procedures.